Threo-dops controlled release formulation

ABSTRACT

The present invention relates to pharmaceutical formulations for the controlled delivery of threo-3-(3,4-dihydroxyphenyl)serine (threo-DOPS) and derivatives of it. Such formulations can contain an extended or slow release component that maintains therapeutic concentration of threo-DOPS in the blood plasma over a prolonged time period. They can be further combined with an immediate release formulation to produce a product that, when administered to a patient in need thereof, results in substantially steady levels of active drug, eliminating the sharp peaks and troughs in blood plasma drug levels experienced with the existing threo-DOPS formulations.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 11/698,974, filed Jan. 29, 2007, which is a continuation ofU.S. patent application Ser. No. 10/556,388, filed Nov. 10, 2005, whichclaims priority to International Patent Application No.PCT/US2004/014770, filed May 12, 2004, and U.S. Provisional PatentApplication No. 60/469,634, filed May 12, 2003, the disclosures of whichare incorporated herein by reference in their entireties.

DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical formulations for thecontrolled delivery of threo-3-(3,4-dihydroxyphenyl)serine (threo-DOPS),and derivatives thereof. Threo-DOPS exists as the optically active L-and D-forms and the racemic DL form. The L-threo-DOPS is preferred forthe purposes of this invention. Such formulations can contain anextended or slow release component that maintains therapeuticconcentration of threo-DOPS in the blood plasma over a prolonged timeperiod. They can be further combined with an immediate releaseformulation to produce a product that, when administered to a patient inneed thereof, results in a rapid attainment of a therapeutic effect,followed by substantially steady levels of active drug, eliminating thesharp peaks and troughs in blood plasma drug levels experienced with theexisting threo-DOPS formulations. These formulation are especiallyuseful in the treatment of conditions associated with norepinephrine(NE) dysfunction, and which benefit from the controlled release ofthreo-3-(3,4-dihydroxyphenyl)serine compounds, such as the painassociated with migraines, and disorders associated with sympatheticnervous system dysfunction such as orthostatic hypotension, orthostaticintolerance, etc.

A pharmaceutical formulation of the present invention includes acontrolled release pharmaceutical formulation, comprising: an effectiveamount of threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, ora pharmaceutically-acceptable salt thereof, in an extended release form.A controlled release formulation can be effective for any desired periodof time, e.g., oral dosage units can be produced that are effective foronce-daily, twice a day (about every 12 hours), or three times (aboutevery 8 hours) a day administration.

The phrase “controlled release” indicates that the release of the activeingredient is regulated or modulated to achieve a desired rate ofdelivery into the systemic circulation. A controlled release formulationcan be pulsed, delayed, extended, slow, steady, immediate, rapid, fast,etc. It can comprise one or more release formulations, e.g. extended-and immediate-release components. For example, to prevent pain, such asthe pain associated with migraine headaches, an oral controlled releaseformulation can comprise a plurality of components positioned in anysuitable arrangement, e.g., comprising a “free” drug in a rapidlysoluble polymer film on the outside of the dosage unit to achieve animmediate therapeutic effect, and an extended release delivery system inthe core of the unit to produce steady state concentrations of drug toprevent recurrence of the pain. A formulation can be a composition ofmatter, a device, a patch, multi-layered or multi-configured products,etc.

The terms “extended release”, “immediate release”, etc., have theirconventional meanings. An extended release composition is one in whichthe active ingredient is not released immediately in its active form,but is slowly and controllably discharged from the dosage unit. Thekinetics of the extended release are influenced by the choice of thedelivery system, amount of the active ingredient, dissolution rate ofthe drug, compartment in which release occurs (e.g., with oral deliverysystems, this is the gastrointestinal tract), absorption of drug fromthe site of release into the systemic circulation, drug distributionfrom the systemic circulation, etc. An immediate release formulation canbe used to deliver the equivalent of a “bolus” to the body, releasingthe active form of the drug directly into the targeted physiologicalcompartment (e.g. the GI tract) to achieve rapid systemic availability.

Any suitable extended release delivery system can be used in accordancewith the present invention to achieve the slow release of threo-DOPS.Several are discussed below, but any effective system can be usedwithout limitation.

1. Dissolution controlled release. Drug particles or granules that havea reasonable aqueous solubility, such as threo-DOPS, can be coated with,or embedded in, a slowly soluble material. The coated particles orgranules can subsequently be compressed into tablets or filled into hardgelatin capsules. Drug can also be applied to the surface of non-pareilseeds, which can then be coated and formulated into either tablets orcapsules.

Coating materials include, but are not limited to, shellacs, beeswax,glyceryl monostearate, glyceryl palmostearate, stearyl alcohol,ethylcellulose, cellulose acetate phthalate, acrylic resins,methacrylate hydrogels, methylmethacrylate, polymethacrylate, polylacticacid, polyvinyl chloride, polyvinyl chloride, polymethacrylate,hydroxypropylmethylcellulose, polyethylene glycols,carboxymethylcellulose, sodium carboxymethylcellulose, etc.

2. Diffusion controlled release. Two main types of diffusion controlledsystems are typically used: reservoir devices and matrix devices. In areservoir device, a water-insoluble polymeric material surrounds adrug-containing core, which can be a tablet, or particles or granulesthat are subsequently formulated into a tablet or a capsule. Materialsused as coatings in reservoir devices includehydroxypropylcellulose/polyvinyl acetate combinations, polyethyleneglycol/ethylcellulose combinations, ethylcellulose, and poly(hydroxymethacrylate).

With matrix devices, the drug is dispersed in an insoluble matrixconsisting of such materials as hydrated methylcellulose, carnauba waxand stearyl alcohol combinations, carbopol, glyceryl tristearate, methylacrylate/methyl methacrylate combinations, and polyvinyl chloride andpolyethylene, alone and in combination.

3. Diffusion and dissolution controlled release. In this deliverysystem, the drug core is encased by a partially-soluble membrane.Dissolution of the soluble portion of the membrane facilitates diffusionof drug through the resultant pores of the polymer coat. An example ofthis type of coating system is ethylcellulose/methylcellulosecombinations.

4. Ion-exchange resins. This approach is based on the presence of ionsin the gastrointestinal tract which will exchange with the drug ionspresent in the resin. The drug-charged resin is prepared by mixing theresin with a solution of the drug, followed by washing and then dryingto form particles or beads. These are then filled into gelatin capsulesor suspended in an appropriate vehicle; prior to this step, they may befilm-coated using one or more of the agents listed in sections 1 and 2above. In one such system, drug-containing resin particles are coatedwith polyethylene 4000 and then with ethylcellulose.

5. pH-independent release. The addition of buffers to the drug deliverysystem can be utilized in such a concentration so as to cause the drugto be released at a rate that is independent on the pH in thegastrointestinal tract.

6. Osmotically controlled release. In this type of delivery system, acore containing the drug and an appropriate amount of an osmoticallyactive salt is surrounded by a semipermeable membrane that is both rigidand non-swelling. The membrane is permeable to gastrointestinal fluidbut impermeable to the drug in solution. Following administration,gastrointestinal fluids diffuse across the semipermeable membrane,thereby dissolving the drug and osmotically active salt to set up anosmotic pressure within the delivery system. Drug solution is thenpushed through a laser-drilled orifice in to the gastrointestinal tractat a constant (zero order) rate until all of the osmotically active saltis depleted.

7. Altered density formulations. This approach relies on the formationof a low density, buoyant, drug-containing tablet matrix. As a result,the delivery system tends to remain floating on top of the stomachcontents, dispensing drug in a uniform manner.

In an immediate release component, the release kinetics are largelydependent on the solubility of threo-DOPS. The active drug can be mixedwith any conventional soluble excipient (such as lactose), or formulatedwith a soluble polymer that readily and directly dissolves in thetargeted compartment (e.g., GI tract). The threo-DOPS can also bemodified to improve its solubility, e.g., by physical (micronized toreduce particle size) treatment, the use of permeation enhancers, orchemical treatment.

Threo-3-(3,4-dihydroxyphenyl)serine (also known as threo-DOPS ordroxidopa) is a synthetic amino acid precursor of NE (Freeman R., Clin.Neuropharm., 14, 296-304, 1991). It has four stereoisomers,L-threo-DOPS, D-threo-DOPS, L-erythro-DOPS, and D-erythro-DOPS. Of thefour, L-threo-DOPS is preferred, but a racemate can also be used.L-threo-DOPS is directly converted to NE via the actions of dopadecarboxylase (DDC) (also known as L-aromatic amino acid decarboxylaseor AAAD). Peak plasma levels of L-threo-DOPS occur 3 hour after oralingestion whereas peak NE levels occur 5 hours after ingestion.Increased plasma levels of both molecules remain at least 12 hours afteroral administration of L-threo-DOPS(S Suzuki T, Higa S, Sakoda S, UejiM, Hayashi A, Takaba Y, Nakajima A.; Eur J Clin Pharmacol 1982;23(5):463-8). Specific uptake of threo-DOPS has also been demonstratedin microvessel preparations (Hardebo J E, Falck B, Owman C. Acta PhysiolScand 1979 October; 107(2):161-7).

Any effective amount of threo-3-(3,4-dihydroxyphenyl)serine can used,e.g., from about 10 mg to about 1000 mg per day, about 50 mg to about700 mg per day, about 100 to about 500 mg per day, about 100 to about300 mg per day, etc. An effective amount is a quantity of threo-DOPSthat is useful for achieving the desired therapeutic effect, e.g.,preventing pain, maintaining blood pressure, preventing the reoccurrenceof a norepinephrine dysfunctional disorder. Effective amounts can bedetermined routinely, and may vary depending upon the age, health,gender, and weight of a patient, as well as the severity, frequency, andduration of the pain. The choice of the delivery system will also guidethe selection of the amounts used. Amounts can be administered inmultiple doses over the course of the day, e.g., in order to achieve aprophylactic effect, or a single dose in a hybrid extended/immediaterelease form.

Any suitable dosing interval can be used in accordance with the presentinvention. Extended delivery systems can be utilized to achieve a dosinginterval, when orally administered, of once every 24 hours, once every12 hours, etc. The dosage form/delivery system can be a tablet or acapsule suited for extended release, but a sustained release liquid orsuspension can also be used. A controlled release pharmaceuticalformulation can be produced which maintains the release of, and or peakblood plasma levels of, threo-3-(3,4-dihydroxyphenyl)serine, derivativethereof, or salt thereof, over a period of at least 8, 12, 16, 18, 20,24 hours, etc. With this type of formulation, the threo-DOPS can becontinuously released in such a way that it is available and effectivefor maintaining the nerve terminal pools of norepinephrine.

A dissolution controlled release delivery system can be utilized inaccordance with the present invention to provide a controlled releasepharmaceutical composition. This delivery system can typically containone or more of the following constituents: 1) active drug; 2) slowlysoluble coating/matrix material (see above, for examples); 3)granulating agent; 4) lubricant (e.g., magnesium stearate); 5)channeling agent (e.g., silicon dioxide); 6) surfactant (e.g., sodiumlauryl sulfate, sodium taurocholate or a polysorbate); and 7) filler(e.g., lactose).

An extended release matrix can comprise any amount of matrix materialthat is necessary to delay the release of threo-DOPS into the systemiccirculation, e.g., amounts can be as low as 5-100% of active drug, butcan also be 2-, 3-, 5-, 10-fold more than active drug, depending uponthe matrix material and the desired delivery kinetics. The activeingredient can be embedded in a matrix that retards dissolution, or theactive ingredient can be coated with a material that has an effect ondissolution, or a combination of both.

As mentioned earlier, an immediate release component can be associatedwith the extended release component to form a multi-layered orcombination system having properties of both. This type of controlledrelease system can provide an immediate bolus to facilitate the fillingof the depleted nerve terminals with norepinephrine, and then a slowrelease component to maintain threo-DOPS in the circulating blood atlevels effective to conserve nerve terminal norepinephrine pools and/orto prevent sympathetic nervous system dysfunction.

A controlled release formulation of threo-DOPS can comprise a quantityof an immediate release preparation of threo-DOPS (or derivativesthereof, or pharmaceutically active salts thereof) combined with aquantity of an extended (slow or delayed) release threo-DOPS (orderivatives thereof, or pharmaceutically active salts thereof). Theimmediate release component can obtain a maximal release of threo-DOPSwithin approximately 1-3 hours after administration, and then falltoward baseline levels. The extended release component can show amaximal release of threo-DOPS between approximately 6-24 hours afteradministration. The extended release component can contain multiple anddifferent extended release formulations to broaden the time over whichthe threo-DOPS is available in active form in the blood stream, e.g.,having extended components that have maximal release at 6 hours, 12hours; and 18 hours, respectively. This can be accomplished by creatingmulti-layered or multi-component dosage units, where each layer orcomponent displays different dissolution kinetics, or by mixingdifferent immediate and extended release components in a single capsuleor tablet. Extended delivery systems can also be utilized that releaseactive drug at roughly the same rate (e.g., zero-order kinetics) for thepredetermined delivery period (6, 12, 18, 24 hours, etc.), e.g., usingan osmotic delivery system. Effective amounts incorporated into each ofthe components can be determined routinely. For example, based on thetotal weight of threo-DOPS (active drug) in the dosage unit, from about15-55% can be in the immediate release form and from about 45-85% can bein the extended and slow release form, e.g., about 35% in immediate formand 65% in extended release form

Threo-3-(3,4-dihydroxyphenyl)serine can be prepared according to anysuitable method. These processes include those described in, e.g., U.S.Pat. Nos. 4,480,109, 4,562,263 and 5,864,041. It can be used as aracemic or optically active isomer, e.g., L-threo-DOPS.

Pharmaceutically-acceptable salts of threo-3-(3,4-dihydroxyphenyl)serinecan also be used, including addition salts, e.g., inorganic acids, suchas hydrochloric acid, hydrobromic acid, and sulfuric acid, and organicacids, such as fumaric acid, citric acid, tartaric acid, and succinicacid.

Any pharmacologically active derivative ofthreo-3-(3,4-dihydroxyphenyl)serine can be used. These include, e.g.,N-methyl-3-(3,4-dihydroxyphenyl)serine alkyl esters, such asN—methyl-D,L-threo-3-(3,4-dihydroxyphenyl)serine andN-methyl-L-threo-3-(3,4 dihydroxyphenyl)serine, lower alkyl esters,methyl esters, ethyl esters, n-propyl esters, isopropyl esters, etc., asdescribed in U.S. Pat. No. 5,288,898.

In addition to the substances already mentioned, active agents can befurther combined with any other suitable additive or pharmaceuticallyacceptable carrier. Such additives include any of the substances alreadymentioned, as well as any of those used conventionally, such as thosedescribed in Remington: The Science and Practice of Pharmacy (Gennaroand Gennaro, eds, 20^(th) edition, Lippincott Williams & Wilkins, 2000);Theory and Practice of Industrial Pharmacy (Lachman et al., eds., 3^(rd)edition, Lippincott Williams & Wilkins, 1986); Encyclopedia ofPharmaceutical Technology (Swarbrick and Boylan, eds., 2^(nd) edition,Marcel Dekker, 2002).

These are generally referred to herein as “pharmaceutically acceptablecarriers” to indicate they are combined with the active drug and can beadministered safely to a subject for therapeutic or prophylacticpurposes. These include, but are not limited to, antioxidants,preservatives, dyes, tablet-coating compositions, plasticizers, inertcarriers, excipients, polymers, coating materials, osmotic barriers,devices and agents which slow or retard solubility, etc.

The active agent of this invention can be in any suitable form, withoutlimitation. Forms suitable for oral use, include, but are not limitedto, tablets troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, solutions, syrupsand elixirs. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions.

The present invention relates to methods of treating a disease in asubject in need thereof, comprising: administering a controlled releasepharmaceutical formulation, comprising an effective amount ofthreo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or apharmaceutically-acceptable salt thereof, in an extended release form.The term “treating” is used conventionally, e.g., the management or careof a subject for the purpose of combating, alleviating, reducing,relieving, improving, etc., a disorder or disease. Diseases that can betreated in accordance with the present invention include, but are notlimited to, with sympathetic nervous system dysfunction, Asthma,Hypersensitivity cough, Allergic Rhinitis/nasal congestion, AnorexiaNervosa, Congestive Heart Failure, Chronic Fatigue Syndrome, Depression,Erectile dysfunction, Essential Tremor, Irritable Bowel Syndrome,Migraine, Obesity, Orthostatic Hypotension, Orthostatic Intolerance,Pain, Premenstrual Syndrome/Premenstrual Dysphoric Disorder, Reynaud'sphenomenon, Reflex Sympathetic Dystrophy, Overactive/neurogenic bladder,etc.

The examples below illustrate tablet and capsule extended releaseformulations comprising threo-DOPS. Tablets can be made conventionally,e.g., as described in Tablet Manufacture, Encyclopedia of PharmaceuticalTechnology, Marcel Dekker, Inc., 2002, Pages 2713-2732. Variousdiluents, granulating fluids, glidants, etc, are described therein.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. The entiredisclosure of all patents and publications cited herein are herebyincorporated by reference in their entirety.

EXAMPLES

1. An extended release hydrophilic matrix formulation prepared by wetgranulation using a high shear mixer and compressed into tabletscontaining:

L-threo-DOPS 100 to 800 mg Hydroxypropylmethylcellulose (HPMC) 5 to 45%Lactose 5 to 20% Magnesium stearate  0 to 1.5% Silicon dioxide  0 to0.5% Granulation fluid q.s.

The drug, polymer, and filler are dry blended in a high shear mixer for5 minutes, at which time sufficient granulation fluid is added toproduce a wet granulation that is subsequently dried, screened, blendedwith lubricant, and compressed to form tablets.

2. An extended release hydrophilic matrix formulation prepared by wetgranulation using a high shear mixer and compressed into tablets, ontowhich is applied additional L-threo-DOPS dispersed in an immediaterelease polymeric film coat containing:

L-threo-DOPS  25 to 300 mg Ethylcellulose 0 to 5.0%Hydroxypropylmethylcellulose 0 to 3.0% Triethyl citrate 0 to 2.0%Aqueous ethanol q.s.

The drug, polymer, and filler are dry blended in a high shear mixer for5 minutes, at which time sufficient granulation fluid is added toproduce a wet granulation that is subsequently dried, screened, blendedwith lubricant, and compressed to form tablets. The tablets are thenspray coated with a polymer solution containing dispersed L-threo-DOPS,sufficient to deliver the required immediate release dose.

3. An extended release hydrophilic matrix formulation prepared by wetgranulation using a high shear mixer and filled into hard gelatincapsules containing:

L-threo-DOPS 100 to 800 mg Hydroxypropylmethylcellulose (HPMC) 5 to 45%Lactose 5 to 20% Magnesium stearate  0 to 1.5% Silicon dioxide  0 to0.5% Granulation fluid q.s.

The drug, polymer, and filler are dry blended in a high shear mixer for5 minutes, at which time sufficient granulation fluid is added toproduce a wet granulation that is subsequently dried, screened, blendedwith lubricant, and filled into hard gelatin capsules.

4. An extended release hydrophilic Matrix-formulation prepared by wetgranulation using a high shear mixer and blended with an immediaterelease formulation containing the following before being filled intohard gelatin capsules:

L-threo-DOPS  25 to 300 mg Lactose 20 to 40% Microcrystalline Cellulose 5 to 15% Magnesium stearate   0 to 1.5% Silicon dioxide   0 to 0.5%Granulation fluid q.s.

The drug and fillers are dry blended in a high shear mixer for 5minutes, at which time sufficient granulation fluid is added to producea wet granulation that is subsequently dried, screened, and blended withlubricant. An appropriate blend of the extended release formulation andthe immediate release formulation are prepared and filled into hardgelatin capsules.

5. An extended release hydrophilic matrix formulation prepared by wetgranulation using a fluidized bed granulator and compressed into tabletscontaining:

L-threo-DOPS  100 to 800 mg Polyvinyl alcohol 20 to 60% Sodium Chloride10 to 30% Lactose 10 to 25% Granulation fluid (e.g.,Hydroxypropylcellulose, q.s. HPC, 5% solution) Magnesium stearate 0 to1.5% Silicon dioxide 0 to 0.5%

The drug, polymer, and fillers are dry blended, and then granulated in afluidized bed granulator using sufficient granulation fluid to produce awet granulation that is subsequently dried, screened, blended withlubricant, and compressed to form tablets.

6. An extended release hydrophilic matrix formulation prepared by wetgranulation using a fluidized bed granulator and compressed intotablets, onto which is applied additional L-threo-DOPS dispersed in animmediate release polymeric film coat containing:

L-threo-DOPS  25 to 300 mg Ethylcellulose 0 to 5.0%Hydroxypropylmethylcellulose 0 to 3.0% Triethyl citrate 0 to 2.0%Aqueous ethanol q.s.

The drug, polymer, and fillers are dry blended, and then granulated in afluidized bed granulator using sufficient granulation fluid to produce awet granulation that is subsequently dried, screened, blended withlubricant, and compressed to form tablets. The tablets are then spraycoated with a polymer solution containing dispersed L-threo-DOPS,sufficient to deliver the required immediate release dose.

7. An extended release hydrophilic matrix formulation prepared by wetgranulation using a high shear mixer and filled into hard gelatincapsules containing:

L-threo-DOPS  100 to 800 mg Polyvinyl alcohol 20 to 60% Sodium chloride10 to 30% Lactose 10 to 25% Granulation fluid (hydroxypropylcellulose,q.s. HPC, 5% solution) Magnesium stearate   0 to 1.5% Silicon dioxide  0 to 0.5%

The drug, polymer, and fillers are dry blended in a high shear mixer for5 minutes, at which time sufficient granulation fluid is added toproduce a wet granulation that is subsequently dried, screened, blendedwith lubricant, and compressed to form tablets.

8. An extended release hydrophilic matrix formulation prepared by wetgranulation using a high shear mixer and blended with an immediaterelease formulation containing the following before being filled intohard gelatin capsules:

L-threo-DOPS  25 to 300 mg Lactose 20 to 40% Microcrystalline Cellulose 5 to 15% Magnesium stearate   0 to 1.5% Silicon dioxide   0 to 0.5%Granulation fluid q.s.

The drug and fillers are dry blended in a high shear mixer for 5minutes, at which time sufficient granulation fluid is added to producea wet granulation that is subsequently dried, screened, and blended withlubricant. An appropriate blend of the extended release formulation andthe immediate release formulation are prepared and filled into hardgelatin capsules.

9. An extended release hydrophilic matrix formulation prepared by wetgranulation using a fluidized bed granulator and compressed into tabletscontaining:

L-threo-DOPS  100 to 800 mg Hydroxypropylmethylcellulose (HPMC) 10 to50% Lactose 10 to 25% Dibasic calcium phosphate  0 to 50%Microcrystalline Cellulose  0 to 25% Granulation Fluid(Polyvinylpyrrolidone, PVP, q.s. 4% solution orHydroxypropylmethylcellulose, HPMC, 3% solution) Magnesium stearate   0to 1.5% Silicon dioxide   0 to 5.0%

The drug, polymer, and fillers are dry blended, and then granulated in afluidized bed granulator using sufficient granulation fluid to produce awet granulation that is subsequently dried, screened, blended withlubricant, and compressed to form tablets.

10. An extended release hydrophilic matrix formulation prepared by wetgranulation using a high fluidized bed granulator and compressed intotablets, onto which is applied additional L-threo-DOPS dispersed in animmediate release polymeric film coat containing:

L-threo-DOPS  25 to 300 mg Ethylcellulose 0 to 5.0%Hydroxypropylmethylcellulose 0 to 3.0% Triethyl citrate 0 to 2.0%Aqueous ethanol q.s.

The drug, polymer, and fillers are dry blended, and then granulated in afluidized bed granulator using sufficient granulation fluid to produce awet granulation that is subsequently dried, screened, blended withlubricant, and compressed to form tablets. The tablets are then spraycoated with a polymer solution containing dispersed L-threo-DOPS,sufficient to deliver the required immediate release dose.

1. A pharmaceutical formulation, comprising: an effective amount ofthreo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or apharmaceutically-acceptable salt thereof, in an extended release formadapted for release over a period of time of at least 6 hours bydissolution controlled release, diffusion controlled release, ordissolution and diffusion controlled release; and an effective amount ofthreo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or apharmaceutically-acceptable salt thereof, in an immediate release form;wherein the formulation is adapted for oral delivery.
 2. Thepharmaceutical formulation of claim 1, wherein the pharmaceuticalformulation comprises a slowly soluble material which is selected fromthe group consisting of: ethylcellulose, cellulose acetate phthalate,acrylic resins, methacrylate hydrogels, methylmethacrylate,polymethacrylate, polylactic acid, polyvinyl chloride,hydroxypropylmethylcellulose, polyethylene glycols,carboxymethylcellulose, and sodium carboxymethylcellulose.
 3. Thepharmaceutical formulation of claim 1, wherein the pharmaceuticalformulation is suitable for once-daily administration.
 4. Thepharmaceutical formulation of claim 1, wherein the pharmaceuticalformulation is suitable for twice- or three-times daily administration.5. The pharmaceutical formulation of claim 1, wherein the formulationcomprises 45-85% by weight of the threo-3-(3,4-dihydroxyphenyl)serine, aderivative thereof, or a pharmaceutically-acceptable salt thereof, inthe extended release form.
 6. The pharmaceutical formulation of claim 1,wherein the formulation comprises 15-55% by weight of thethreo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or apharmaceutically-acceptable salt thereof, in the immediate release form.7. The pharmaceutical formulation of claim 1, wherein the extendedrelease form comprises an excipient selected from the group consistingof lubricants, channeling agents, surfactants, fillers, and combinationsthereof.
 8. The pharmaceutical formulation of claim 7, wherein theexcipient is selected from the group consisting of silicon dioxide,magnesium stearate, sodium lauryl sulfate, sodium taurocholate,polysorbate, lactose, hydroxypropylmethylcellulose, ethylcellulose,triethyl citrate, microcrystalline cellulose, polyvinyl alcohol, sodiumchloride, dibasic calcium phosphate, polyvinylpyrrolidone, and mixturesthereof.
 9. The pharmaceutical formulation of claim 1, wherein thethreo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or apharmaceutically-acceptable salt thereof, in an extended release form isprovided in particulate form.
 10. The pharmaceutical formulation ofclaim 9, wherein the particles are coated with a water-insolublepolymeric membrane coating.
 11. The pharmaceutical formulation of claim10, wherein the water-insoluble polymeric membrane coating comprises oneor more coating materials selected from the group consisting ofshellacs, beeswax, glyceryl monostearate, glyceryl palmostearate,stearyl alcohol, ethylcellulose, cellulose acetate phthalate, acrylicresins, methacrylate hydrogels, methylmethacrylate, polymethacrylate,polylactic acid, polyvinyl chloride, hydroxypropylmethylcellulose,polyethylene glycols, carboxymethylcellulose, sodiumcarboxymethylcellulose, and mixtures thereof.
 12. The pharmaceuticalformulation of claim 1, wherein the extended release form furthercomprises an osmotically active salt.
 13. The pharmaceutical formulationof claim 1, wherein the formulation provides for maximal release of theimmediate release form within about 1 to about 3 hours afteradministration, and provides for maximal release of the extended releaseform between about 6 to about 24 hours after administration.
 14. Thepharmaceutical formulation of claim 1, wherein one or both of theextended release form and immediate release form of thethreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, is released at a rate that isindependent of the pH in the gastrointestinal tract.
 15. Apharmaceutical formulation comprising: an effective amount ofthreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, in an extended release formadapted for release over a period of at least 6 hours by continuousdiffusion controlled release, wherein the extended release formcomprises particles formed of the threo-3-(3,4-dihydroxyphenyl)serine,or a derivative or pharmaceutically-acceptable salt thereof, applied toa surface of non-pareil seeds, and wherein the formulation is adaptedfor oral delivery.
 16. The pharmaceutical formulation of claim 15,wherein the extended release form further comprises an excipientselected from the group consisting of lubricants, channeling agents,surfactants, and fillers.
 17. The pharmaceutical formulation of claim16, wherein the excipient is selected from the group consisting ofsilicon dioxide, magnesium stearate, sodium lauryl sulfate, sodiumtaurocholate, polysorbate, lactose, hydroxypropylmethylcellulose,ethylcellulose, triethyl citrate, microcrystalline cellulose, polyvinylalcohol, sodium chloride, dibasic calcium phosphate,polyvinylpyrrolidone, and mixtures thereof.
 18. The pharmaceuticalformulation of claim 15, wherein the particles further comprise awater-insoluble polymeric membrane coating.
 19. The pharmaceuticalformulation of claim 18, wherein the water-insoluble polymeric membranecoating comprises one or more coating materials selected from the groupconsisting of shellacs, beeswax, glyceryl monostearate, glycerylpalmostearate, stearyl alcohol, ethylcellulose, cellulose acetatephthalate, acrylic resins, methacrylate hydrogels, methylmethacrylate,polymethacrylate, polylactic acid, polyvinyl chloride,hydroxypropylmethylcellulose, polyethylene glycols,carboxymethylcellulose, sodium carboxymethylcellulose, and mixturesthereof.
 20. The pharmaceutical formulation of claim 15, wherein theparticles comprise the non-pareil seeds coated with a compositioncomprising the threo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, a channeling agent, asurfactant, and a filler.
 21. The pharmaceutical formulation of claim20, wherein the channeling agent is silicon dioxide, the surfactant isselected from the group consisting of sodium lauryl sulfate, sodiumtaurocholate, polysorbates, and combinations thereof, and the filler isselected from the group consisting of lactose, sodium chloride, triethylcitrate, and combinations thereof.
 22. The pharmaceutical formulation ofclaim 15, wherein the extended release form of thethreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, is released at a rate that isindependent of the pH in the gastrointestinal tract.
 23. Thepharmaceutical formulation of claim 15, wherein the extended releaseform further comprises an osmotically active salt.
 24. Thepharmaceutical formulation of claim 15, further comprising an effectiveamount of threo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, ora pharmaceutically-acceptable salt thereof, in an immediate releaseform.
 25. The pharmaceutical formulation of claim 24, wherein theformulation provides for maximal release of the immediate release formwithin about 1 to about 3 hours after administration, and provides formaximal release of the extended release form between about 6 to about 24hours after administration.
 26. The pharmaceutical formulation of claim24, wherein the immediate release form of thethreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, is released at a rate that isindependent of the pH in the gastrointestinal tract.
 27. Thepharmaceutical formulation of claim 15, wherein the pharmaceuticalformulation releases the threo-3-(3,4-dihydroxyphenyl)serine, aderivative thereof, or a pharmaceutically-acceptable salt thereof, atroughly the same rate for a predetermined delivery period of at leastabout 6 hours.
 28. The pharmaceutical formulation of claim 15, whereinthe formulation is suitable for once daily administration.
 29. Thepharmaceutical formulation of claim 15, wherein the formulation issuitable for twice a day or three times a day administration.
 30. Apharmaceutical formulation in an extended release form comprising: aneffective amount of threo-3-(3,4-dihydroxyphenyl)serine, or a derivativeor pharmaceutically-acceptable salt thereof, a coating/matrix material,a channeling agent, and a filler, wherein the formulation providescontinuous release of threo-3-(3,4-dihydroxyphenyl)serine, or aderivative or pharmaceutically-acceptable salt thereof, over a period ofat least 6 hours, and wherein the formulation is adapted for oraldelivery.
 31. The pharmaceutical formulation of claim 30, wherein theformulation provides continuous diffusion controlled release of thethreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof.
 32. The pharmaceuticalformulation of claim 31, wherein thethreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, is provided in a coresurrounded by a water-insoluble polymeric material.
 33. Thepharmaceutical formulation of claim 30, wherein the formulation providescontinuous dissolution controlled release of thethreo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof.
 34. The pharmaceuticalformulation of claim 30, wherein the coating/matrix material is selectedfrom the group consisting of shellacs, beeswax, glyceryl monostearate,glyceryl palmostearate, stearyl alcohol, ethylcellulose, celluloseacetate phthalate, acrylic resins, methacrylate hydrogels,methylmethacrylate, polymethacrylate, polylactic acid, polyvinylchloride, hydroxypropylmethylcellulose, polyethylene glycols,carboxymethylcellulose, sodium carboxymethylcellulose, and mixturesthereof.
 35. The pharmaceutical formulation of claim 30, wherein thechanneling agent comprises silicon dioxide.
 36. The pharmaceuticalformulation of claim 30, wherein the filler is selected from the groupconsisting of lactose, sodium chloride, triethyl citrate, andcombinations thereof.
 37. The pharmaceutical formulation of claim 30,further comprising a surfactant.
 38. The pharmaceutical formulation ofclaim 37, wherein the surfactant is selected from the group consistingof sodium lauryl sulfate, sodium taurocholate, polysorbates, andcombinations thereof.
 39. The pharmaceutical formulation of claim 30,further comprising a lubricant.
 40. The pharmaceutical formulation ofclaim 39, wherein the lubricant comprises magnesium stearate.
 41. Thepharmaceutical formulation of claim 30, further comprising a granulatingagent.
 42. The pharmaceutical formulation of claim 30, furthercomprising one or more components selected from the group consisting ofantioxidants, preservatives, dyes, plasticizers, inert carriers, osmoticbarriers, and combinations thereof.
 43. The pharmaceutical formulationof claim 30, further comprising an effective amount ofthreo-3-(3,4-dihydroxyphenyl)serine, a derivative thereof, or apharmaceutically-acceptable salt thereof, in an immediate release form.44. The pharmaceutical formulation of claim 43, wherein the immediaterelease form of the threo-3-(3,4-dihydroxyphenyl)serine, or a derivativeor pharmaceutically-acceptable salt thereof, is released at a rate thatis independent of the pH in the gastrointestinal tract.
 45. Thepharmaceutical formulation of claim 30, wherein the extended releaseform of the threo-3-(3,4-dihydroxyphenyl)serine, or a derivative orpharmaceutically-acceptable salt thereof, is released at a rate that isindependent of the pH in the gastrointestinal tract.
 44. Thepharmaceutical formulation of claim 43, wherein the formulation providesfor maximal release of the immediate release form within about 1 toabout 3 hours after administration, and provides for maximal release ofthe extended release form between about 6 to about 24 hours afteradministration.
 45. The pharmaceutical formulation of claim 30, whereinthe formulation is suitable for once daily administration.
 46. Thepharmaceutical formulation of claim 30, wherein the formulation issuitable for twice a day or three times a day administration.